3-mercaptoandrostan-17beta-ol and its acylate



3,265,713 Patented August 9, W66

The present invention relates to S-marcaptoandrostan- 178-ol and its acylate represented by the formula:

where in the ripple mark represents'aor p-configuration and R and R are each a hydrogen atom or an acyl group. The said acyl group is preferably derived from carboxylic acids having from one to about twelve can bon atoms, conventionally employed in the steroid art, and having a molecular weightless than about 200. Representative of the acyl group which can be present are lower alkanoyl (e.g. formyl, acetyl, propionybbutyryl, isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl), lower alkenoyl (e.g. crotonoyl, undecenoyl), carboxy(lower)all anoyl (e.g. succinyl), cycloalkyl- (lower)aikanoyl (e.g. B-cyclopentylpropionyl, fl-cyclohexylpropionyi), monocarbocyclic aroyl (e.g. benzoyl, p toluyl, p nitrobenzoyl, 3,4,5 trimethoxybenzoyl), monocarbocyclic aryl(lower)alkanoyl or alkenoyl (e.g. phenylacetyl, fi-phenylpropionyl, cinnamoyl) and monocarbocyclic ary1oxy(lower)alkanoyl (e.g. p chlorophenoxyacetyl).

It is a basic object of the present invention to embody 3 mercaptoandrostan 175 01 and its acylate of Formula. 1. Another object of this invention is to embody 3 mercaptoandrostan 17,3 01 and its acylate of Formula I having physiological activity. A further object of the invention is to embody a process for preparing 3 mercaptoandrostan l7fi 01 and its acylate of i orn'iula I. These and other objects will be apparent to those conversant with the art to which the present invention pertains from the subsequent descripnon.

According to the present invention, the objective 3- mercaptoandrostan 17,8 01 and its acylate of Formula I are prepared by reducing 3 thiocyanatoandrostanl7-one, or 3 thiocyanatoandrostan 17 3 01 or its acylate with a reducing agent, if necessary, followed by acylation. Such conversions may be represented by the following formulae:

i ne 1 (III) NCSMN wherein R" and R'" are each an acyl group as illustrated above.

The starting materials, i.e. 3 thiocyanatoandrostanl7-one of Formula II, 3 thiocyanatoandrostan 17B- 01 of Formula III and 3 thiocyanatoandrostan 17B- 01 17-acylate of Formula IV, may be each prepared by reacting the corresponding 3 toluenesulfonyloxysteroid with thiocyanate ion in an aprotic solvent [Henbest et al.: J. Chem. Soc., p. 954 (1962)].

The reduction is usually effected by treating the starting material of Formula II, III or IV with a reducing agent such as a metallic hydride (e.g. lithium aluminum hydride (potassium aluminum hydride, sodium borohydride, lithium borohydride) in an inert solvent (e.g. ether, d-ioxane, tetrahydrofuran, methanol, ethanol, water) at a wide range of temperature from room temperature (10 to 30 C.) to reflux temperature; The subsequent acylation may be carried out in a convenas needles melting at 160 to 161 C.

tional manner, e.g. treatment with a carboxylic acid anhydride or halide in the presence of an acidic or a basic catalyst.

The thus prepared 3-mercaptoandrostan-17 9-01 and its acylate of Formula l are useful an anti-progestational, ant-i-nterotropic and anti'deciduomatogenic agents.

The following examples set forth presently-preferred embodiments of the present invention.

Example 1 To a suspension of lithium aluminum hydride (150 mg.) in anhydrous ether (10 ml.), there is dropwise added a solution of 3a-thiocyanato-5a-androstan-17-one (308 mg.) in anhydrous ether (30 ml.) at room temperature (10 to 30 C.), and the resulting mixture is stirred for 2 hours. The reaction mixture is acidified with hydrochloric acid and shaken with a mixture of ether and chloroform. The organic solvent layer is evaporated and crystallized from methanol to give 3oz mercapto- 50a androstan 17B oi as crystals melting at 143 to 144 C. Yield, 90%.

The above prepared 3a mercapto 5a androstanl7fl ol is reacted with acetic anhydride in pyridine on a water bath for 2 hours. The reaction mixture is treated in a conventional manner to give 3u-acetylthio- 176 acetyloxy 5oz androstane as crystals melting at 150 to 151 C. (crystallized from methanol).

Exam pl e 2 3B thiocyanato 5a androstan 17 one (1 g.) is reacted with lithium aluminum hydride (0.5 g.) in anhydrous ether (100 ml.) and the reaction mixture treated as in Example 1. Recrystallization of the product from acetone gives 35 mercapto 5a androst-an 17B 01 Yield, 90%.

The above prepared 3,3 mercapto 5a androstan- 173-01 is reacted with acetic anhydride in pyridine at room temperature overnight. The reaction mixture is treated in a conventional manner to give 35 acetylthio- 17,8 acetyloxy 5a androstane as crystals melting at 111 to 112 C. (crystallized from methanol).

Example 3 A solution of 30: thiocyanato 5a androstan 17- one (100 mg.) in a mixture of tetrahydrofuran ml.) and water (i ml.) is refluxed for 4 hours while addition of sodium borohydride (200 mg.) in several times. The reaction mixture is acidified with hydrochloric acid and shaken with a mixture of ether and chloroform. The organic solvent layer is evaporated and crystallized from methanol to give 3a mercapto 5a androstan- 175-01 as crystals melting at 143 to 144 C. Yield, 85%.

Example 4 To a solution of 30a thiocyanato 5oz androstan- 17,8-01 (l g.) in anhydrous tetrahydrofuran (20 ml.), there is dropwise added a solution of lithium aluminum hydride (250 mg.) in anhydrous tetrahydrofuran (100 ml.) while stirring under cooling with ice, and the resulting mixture is stirred for 1 hour at room temperature. The reaction mixture is acidified with hydrochloric acid and shaken with chloroform. The chloro- 4 form layer is washed with water, dried over anhydrous sodium sulfate and the solvent evaporated. The residue is crystallized from methanol to give 30: mercapto- 5a androstan 17B oi as crystals melting at 143 to 144 C. Yield, 92%.

Example 5 To a solution 30/. thiocyanato 5oz androstan 17,3- 01 (1 g.) in methanol (20 ml.), there is added water (0.5 ml.), and the resultant mixture is refluxed for 3 hours while addition of sodium borohydride (l g.) in several times. The reaction mixture is acidified with hydrochloric acid and shaken with chloroform. The chloroform layer is Washed with water, dried over anhydrous sodium sulfate and the solvent evaporated. The residue is crystallized from methanol to give 30:- mercapto 5a androstan 17o 01 as crystals melting at 143 to 144 C. Yield, 88%.

Example 6 A solution of 3a thiocyanato 17,8 acetyloxy- Sa-androstane (500 mg.) in a mixture of tetrahydrofuran (30 ml.) and water (3 ml.) is refluxed for 4 hours while addition of sodium borohydride (500 mg.) in several times. The reaction mixture is acidified with hydrochloric acid and shaken with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate and the solvent evaporated. The residue is crystallized from methanol to give 3a-mercapto- 17 3-acetyIOXy-Sa-androstane as crystals.

The above prepared 3a mercapto 17/3 acetyloxy- 5a-androstane is reacted with propionic anhydride in pyridine on a water bath for 3 hours. The reaction mixture is treated in a conventional manner to give 30cpropionylthio-l7fl-acetyloxy-5a-androstane.

What is claimed is:

ll. A steroid of the formula:

wherein the ripple mark (E) is a generic indication of aand p-configurations and R and R are each a member selected from the group consisting of hydrogen and acyl, the acyl being a carboxylic acyl group having from one to twelve carbon atoms and a molecular weight less than about 200.

2. 3a-mercaptQ-Sa-androstan-l7,3-01.

3. 3ix-acetylthio-17B-acetyloxy-5u-androstane.

4i. 3 3-mercapto-5wandrostan-175-01.

5. Sfl-acetylthio-17fl-acetyloxy-5a-androstane.

No references cited.

LEWIS GOTTS, Primary Examiner. JOHNNIE R. BROWN, Assistant Examiner. 

1. A STEROID OF THE FORMULA: 